Multicellular Networks Research Articles

On the Design of OFDMA-Based FFR-Aided Irregular Cellular Networks With Shadowing

Owing to its high capabilities in terms of spectral efficiency and flexibility, orthogonal frequency division multiple access (OFDMA) has played a crucial role towards the success of 4G cellular systems and an increasing number of actors in the 5G arena strongly advocate for its continuation. OFDMA-based architectures do not introduce intracell interference but, due to the use of very aggressive frequency reuse plans, they must implement some form of inter-cell interference (ICI) control to warrant prescribed levels of quality of service, specially to users located near the cell edge. An efficient technique for mitigating ICI in OFDMA networks is the well-known fractional frequency reuse (FFR) scheme. In FFR, a signal-to-interference-plus-noise ratio threshold is used to categorize mobile stations (MSs) as cell-center or cell-edge MSs. Furthermore, a different number of frequency resources are allocated to cell-center and cell-edge areas according to a prescribed frequency reuse plan. This paper presents an analytical characterization of FFR-aided OFDMA-based multi-cellular networks that, unlike most previous studies, incorporates shadowing effects and, furthermore, considers that base stations are irregularly deployed. This analytical approach can incorporate different scheduling rules and can underpin different designs for which the optimal FFR parameters can be derived. The proposed framework allows the performance evaluation and optimization of any cell in the system by considering the specific network topology, the user association and categorization processes, the spatial density of users and the characteristics of both the fast multipath fading and the spatially correlated slow shadow fading.

Dynamic Fractional Frequency Reuse Diversity Design for Intercell Interference Mitigation in Nonorthogonal Multiple Access Multicellular Networks

Nonorthogonal multiple access (NOMA) is one of the few promising techniques that can ensure the achievement of benefits foreseen in next‐generation 5G wireless networks and beyond. By using superposition coding, NOMA allows multiple users to share the same time and frequency resources, thereby enhancing user connectivity, spectral efficiency, and a considerable increase in user throughput. Interference mitigation is an important consideration in NOMA and is considerably more influencing in multicellular environments. First, a brief description of the impairments that can arise in a NOMA cellular network along with responsible factors is provided. Second, different approaches adopted to minimize these impairments are discussed. Finally, a possible solution is proposed that consists of a coordinated approach between the individual cells in the NOMA domain to minimize interferences and improve user throughput. Adaptive fractional frequency reuse (FFR) is used to allocate distinct frequency resources to edge users of different cells to minimize intercell interference in NOMA. Simulation results prove that the proposed NOMA scheme plays an important role in minimizing impairment effects and enhancing the SINR and the throughput performance of edge users while ensuring fairness in its design.

3D collagen architecture induces a conserved migratory and transcriptional response linked to vasculogenic mimicry

The topographical organization of collagen within the tumor microenvironment has been implicated in modulating cancer cell migration and independently predicts progression to metastasis. Here, we show that collagen matrices with small pores and short fibers, but not Matrigel, trigger a conserved transcriptional response and subsequent motility switch in cancer cells resulting in the formation of multicellular network structures. The response is not mediated by hypoxia, matrix stiffness, or bulk matrix density, but rather by matrix architecture-induced β1-integrin upregulation. The transcriptional module associated with network formation is enriched for migration and vasculogenesis-associated genes that predict survival in patient data across nine distinct tumor types. Evidence of this gene module at the protein level is found in patient tumor slices displaying a vasculogenic mimicry (VM) phenotype. Our findings link a collagen-induced migration program to VM and suggest that this process may be broadly relevant to metastatic progression in solid human cancers.

Agent-based computational model of retinal angiogenesis simulates microvascular network morphology as a function of pericyte coverage.

Define a role for perivascular cells during developmental retinal angiogenesis in the context of EC Notch1-DLL4 signaling at the multicellular network level. The retinal vasculature is highly sensitive to growth factor-mediated intercellular signaling. Although EC signaling has been explored in detail, it remains unclear how PC function to modulate these signals that lead to a diverse set of vascular network patterns in health and disease. We have developed an ABM of retinal angiogenesis that incorporates both ECs and PCs to investigate the formation of vascular network patterns as a function of pericyte coverage. We use our model to test the hypothesis that PC modulate Notch1-DLL4 signaling in endothelial cell-endothelial cell interactions. Agent-based model (ABM) simulations that include PCs more accurately predict experimentally observed vascular network morphologies than simulations that lack PCs, suggesting that PCs may influence sprouting behaviors through physical blockade of endothelial intercellular connections. This study supports a role for PCs as a physical buffer to signal propagation during vascular network formation-a barrier that may be important for generating healthy microvascular network patterns.

Neuroprotective effects of Ginkgo biloba extract and Ginkgolide B against oxygen-glucose deprivation/reoxygenation and glucose injury in a new in vitro multicellular network model.

Acute ischemic stroke (AIS), as the third leading cause of death worldwide, is characterized by its high incidence, mortality rate, high incurred disability rate, and frequent reoccurrence. The neuroprotective effects of Ginkgo biloba extract (GBE) against several cerebral diseases have been reported in previous studies, but the underlying mechanisms of action are still unclear. Using a novel in vitro rat cortical capillary endothelial cell-astrocyte-neuron network model, we investigated the neuroprotective effects of GBE and one of its important constituents, Ginkgolide B (GB), against oxygen-glucose deprivation/reoxygenation and glucose (OGD/R) injury. In this model, rat cortical capillary endothelial cells, astrocytes, and neurons were cocultured so that they could be synchronously observed in the same system. Pretreatment with GBE or GB increased the neuron cell viability, ameliorated cell injury, and inhibited the cell apoptotic rate through Bax and Bcl-2 expression regulation after OGD/R injury. Furthermore, GBE or GB pretreatment enhanced the transendothelial electrical resistance of capillary endothelial monolayers, reduced the endothelial permeability coefficients for sodium fluorescein (Na-F), and increased the expression levels of tight junction proteins, namely, ZO-1 and occludin, in endothelial cells. Results demonstrated the preventive effects of GBE on neuronal cell death and enhancement of the function of brain capillary endothelial monolayers after OGD/R injury in vitro; thus, GBE could be used as an effective neuroprotective agent for AIS/reperfusion, with GB as one of its significant constituents.

Recapitulating in vivo-like plasticity of glioma cell invasion along blood vessels and in astrocyte-rich stroma

Diffuse invasion of glioma cells into the brain parenchyma leads to nonresectable brain tumors and poor prognosis of glioma disease. In vivo, glioma cells can adopt a range of invasion strategies and routes, by moving as single cells, collective strands and multicellular networks along perivascular, perineuronal and interstitial guidance cues. Current in vitro assays to probe glioma cell invasion, however, are limited in recapitulating the modes and adaptability of glioma invasion observed in brain parenchyma, including collective behaviours. To mimic in vivo-like glioma cell invasion in vitro, we here applied three tissue-inspired 3D environments combining multicellular glioma spheroids and reconstituted microanatomic features of vascular and interstitial brain structures. Radial migration from multicellular glioma spheroids of human cell lines and patient-derived xenograft cells was monitored using (1) reconstituted basement membrane/hyaluronan interfaces representing the space along brain vessels; (2) 3D scaffolds generated by multi-layered mouse astrocytes to reflect brain interstitium; and (3) freshly isolated mouse brain slice culture ex vivo. The invasion patterns in vitro were validated using histological analysis of brain sections from glioblastoma patients and glioma xenografts infiltrating the mouse brain. Each 3D assay recapitulated distinct aspects of major glioma invasion patterns identified in mouse xenografts and patient brain samples, including individually migrating cells, collective strands extending along blood vessels, and multicellular networks of interconnected glioma cells infiltrating the neuropil. In conjunction, these organotypic assays enable a range of invasion modes used by glioma cells and will be applicable for mechanistic analysis and targeting of glioma cell dissemination.

Optical clearing and fluorescence deep-tissue imaging for 3D quantitative analysis of the brain tumor microenvironment

BackgroundThree-dimensional visualization of the brain vasculature and its interactions with surrounding cells may shed light on diseases where aberrant microvascular organization is involved, including glioblastoma (GBM). Intravital confocal imaging allows 3D visualization of microvascular structures and migration of cells in the brain of mice, however, with limited imaging depth. To enable comprehensive analysis of GBM and the brain microenvironment, in-depth 3D imaging methods are needed. Here, we employed methods for optical tissue clearing prior to 3D microscopy to visualize the brain microvasculature and routes of invasion of GBM cells.MethodsWe present a workflow for ex vivo imaging of optically cleared brain tumor tissues and subsequent computational modeling. This workflow was used for quantification of the microvasculature in relation to nuclear or cellular density in healthy mouse brain tissues and in human orthotopic, infiltrative GBM8 and E98 glioblastoma models.ResultsEx vivo cleared mouse brain tissues had a >10-fold imaging depth as compared to intravital imaging of mouse brain in vivo. Imaging of optically cleared brain tissue allowed quantification of the 3D microvascular characteristics in healthy mouse brains and in tissues with diffuse, infiltrative growing GBM8 brain tumors. Detailed 3D visualization revealed the organization of tumor cells relative to the vasculature, in both gray matter and white matter regions, and patterns of multicellular GBM networks collectively invading the brain parenchyma.ConclusionsOptical tissue clearing opens new avenues for combined quantitative and 3D microscopic analysis of the topographical relationship between GBM cells and their microenvironment.

A synthetic multi-cellular network of coupled self-sustained oscillators.

Engineering artificial networks from modular components is a major challenge in synthetic biology. In the past years, single units, such as switches and oscillators, were successfully constructed and implemented. The effective integration of these parts into functional artificial self-regulated networks is currently on the verge of breakthrough. Here, we describe the design of a modular higher-order synthetic genetic network assembled from two independent self-sustained synthetic units: repressilators coupled via a modified quorum-sensing circuit. The isolated communication circuit and the network of coupled oscillators were analysed in mathematical modelling and experimental approaches. We monitored clustering of cells in groups of various sizes. Within each cluster of cells, cells oscillate synchronously, whereas the theoretical modelling predicts complete synchronization of the whole cellular population to be obtained approximately after 30 days. Our data suggest that self-regulated synchronization in biological systems can occur through an intermediate, long term clustering phase. The proposed artificial multicellular network provides a system framework for exploring how a given network generates a specific behaviour.

Tweety-Homolog 1 Drives Brain Colonization of Gliomas.

Early and progressive colonization of the healthy brain is one hallmark of diffuse gliomas, including glioblastomas. We recently discovered ultralong (>10 to hundreds of microns) membrane protrusions [tumor microtubes (TMs)] extended by glioma cells. TMs have been associated with the capacity of glioma cells to effectively invade the brain and proliferate. Moreover, TMs are also used by some tumor cells to interconnect to one large, resistant multicellular network. Here, we performed a correlative gene-expression microarray and in vivo imaging analysis, and identified novel molecular candidates for TM formation and function. Interestingly, these genes were previously linked to normal CNS development. One of the genes scoring highest in tests related to the outgrowth of TMs was tweety-homolog 1 (TTYH1), which was highly expressed in a fraction of TMs in mice and patients. Ttyh1 was confirmed to be a potent regulator of normal TM morphology and of TM-mediated tumor-cell invasion and proliferation. Glioma cells with one or two TMs were mainly responsible for effective brain colonization, and Ttyh1 downregulation particularly affected this cellular subtype, resulting in reduced tumor progression and prolonged survival of mice. The remaining Ttyh1-deficient tumor cells, however, had more interconnecting TMs, which were associated with increased radioresistance in those small tumors. These findings imply a cellular and molecular heterogeneity in gliomas regarding formation and function of distinct TM subtypes, with multiple parallels to neuronal development, and suggest that Ttyh1 might be a promising target to specifically reduce TM-associated brain colonization by glioma cells in patients.SIGNIFICANCE STATEMENT In this report, we identify tweety-homolog 1 (Ttyh1), a membrane protein linked to neuronal development, as a potent driver of tumor microtube (TM)-mediated brain colonization by glioma cells. Targeting of Ttyh1 effectively inhibited the formation of invasive TMs and glioma growth, but increased network formation by intercellular TMs, suggesting a functional and molecular heterogeneity of the recently discovered TMs with potential implications for future TM-targeting strategies.

A Maximum Likelihood Approach for SSS Detection in LTE Systems

Before establishing a communication link with the serving base station (eNodeB), user equipment (UE) operating in a long-term evolution (LTE) multi-cellular network must acquire some specific information, including the sector identity and cell group identity. For this purpose, two training sequences called primary synchronization signal (PSS) and secondary synchronization signal (SSS) are periodically transmitted in the downlink to convey such information. In this work, we present a novel maximum likelihood (ML) approach for SSS detection assuming that the PSS has been successfully identified at an earlier stage. As we shall see, the resulting scheme turns out to be too complex for practical implementation as it requires perfect knowledge of the channel covariance matrix. Therefore, we look for simpler solutions and propose two reduced-search methods that operate in a mismatched mode. The first scheme exploits channel state information emerging from both the primary and secondary synchronization signals, while the second scheme operates using only the secondary synchronization signal. Numerical analysis indicates that the proposed methods outperform existing alternatives and can be successfully applied even in a severe propagation scenario. The price for such an advantage is a certain increase of the processing requirement.

Sensitivity analysis of FBMC-based multi-cellular networks to synchronization errors and HPA nonlinearities

In this paper, we study the performance of asynchronous and nonlinear FBMC-based multi-cellular networks. The considered system includes a reference mobile perfectly synchronized with its reference base station (BS) and K interfering BSs. Both synchronization errors and high-power amplifier (HPA) distortions will be considered and a theoretical analysis of the interference signal will be conducted. On the basis of this analysis, we will derive an accurate expression of signal-to-noise-plus-interference ratio (SINR) and bit error rate (BER) in the presence of a frequency-selective channel. In order to reduce the computational complexity of the BER expression, we applied an interesting lemma based on the moment generating function of the interference power. Finally, the proposed model is evaluated through computer simulations which show a high sensitivity of the asynchronous FBMC-based multi-cellular network to HPA nonlinear distortions.

Connexin-dependent intercellular stress signaling in tissue homeostasis and tumor development.

1. Connexins and gap junctions protect cells from the microenvironmental stress and are involved in propagation and intracellular processing of stress signals. 2. The quality and quantity of stress stimuli, which may lead to cell adaptation or death by apoptosis, is determined by intrinsic properties of connexins and the cell phenotype. 3. Connexin deficiency increases the resistance of tumor cells to the "outside-in" stress signaling. 4. The connexin-mediated "inside-out" stress signaling participates in tumor cell invasion during the metastatic cascade.

A bionic incremental model of the fashion industry value chain based on a multicellular network

With the development of the fashion industry, it is useful to analyze its value chain increment mechanism in different social environments and economic development situations. In this paper, we propose a bionic increment model of the fashion industry value chain (FIVC) based on a multicellular network structure. First, we summarize the main factors influencing the increment in the FIVC, and regard these as symbiotic biological tissue cells in a multicellular network structure. We then explore the relationships between the cells of different biological tissues in various simulated environments. Furthermore, we analyze the characteristics of the FIVC based on our multicellular network model. A simulated analysis based on a simplified six-cell network is used to demonstrate the flexibility of the bionic increment model. In the six-cell network, the profitability of an enterprise is determined by its four abilities: (1) basic operational ability, (2) human resource utilization, natural resource development and utilization ability, (3) marketing ability, and (4) fashion brand influence, and scientific innovation ability. Through the simulation results, we find that the multicellular tissue network model can effectively simulate the incremental process of the FIVC, which conforms to the intuitive cognition. It can help an enterprise to predict and regulate its value chain increment, and thus has both practical and theoretical significance.

OS1.6 Tumor Microtubes contribute to resistance against surgical lesions, and chemotherapy in malignant glioma

AbstractBackground:The current standard for the treatment of astrocytomas, including glioblastomas, consists of tumor resection, followed by radio- and chemotherapy. As we could recently demonstrate, a dense multicellular tumor network formed by intercellular tumor microtubes (TMs) greatly contributes to radioresistance. The neuronal growth-associated protein 43 (GAP-43) is involved in this mechanism. Here we asked whether similar resistance mechanisms can be found with respect to surgical lesions, and chemotherapy.Methods:Cranial windows were implanted into 8–10 weeks old male NMRI nude mice. Human glioblastoma stem-like cells (GBMSCs; stably transduced with GFP, RFP, YFP, shRNA for GAP-43, control vector, and/or H2B-GFP to label tumor cell nuclei) were stereotactically injected into the mouse’s brain. In established tumors, 100mg/kg temozolomide (TMZ) was applied to mice p.o. for three consecutive days (day 0,1,2). For surgical lesion experiments, a regional injury was set to the brain by a 26 gauge Hamilton syringe.Results:Similar to radiotherapy, GBMSCs that were not part of the TM-connected tumor cell network died in relevant numbers 7 days after chemotherapy, while TM-connected tumor cells survived. The number of TM-connected tumor cells even increased twofold after chemotherapy, which speaks for an adapative resistance mechanism. It is currently under investigation whether knock down of GAP-43 increases overall efficacy of TMZ therapy. After surgical resection, the lesioned area was rapidly re-colonized with TM-extending tumor cells, with a striking increase in tumor cells at the site of lesion that by far extended the tumor cell densitiy in unlesioned tumor areas. Qantification revealed that the tumor cell nuclear density increased to numbers five-fold above values before surfical intervention in this area, evident as early as five days (488.3%; P=0.033; 95% CI, 50.3–726.4), and extending to 14 days (523.9%; P=0.03; 95% CI, 66.7–781.1) after surgical procedure. This apparent,,repair response” gradually diminished with increasing distance to the surgical lesion site. Finally, while dexamethasone did not relevantly change these reponses, GAP-43 knock down reduced them significantly.Conclusion:TMs convey primary and adaptive resistance to TMZ chemotherapy, in accordance to what we have shown before for radiotherapy. They are also involved in a strong repair response at the very site of a surgical lesion. Reducing the ability of gliomas to repair themselves, and to resist genotoxic stress by interfering with TM formation and function appears as a promising avenue to improve treatment efficacies in these callenging diseases.

Communication shapes sensory response in multicellular networks

Collective sensing by interacting cells is observed in a variety of biological systems, and yet, a quantitative understanding of how sensory information is collectively encoded is lacking. Here, we investigate the ATP-induced calcium dynamics of monolayers of fibroblast cells that communicate via gap junctions. Combining experiments and stochastic modeling, we find that increasing the ATP stimulus increases the propensity for calcium oscillations, despite large cell-to-cell variability. The model further predicts that the oscillation propensity increases with not only the stimulus, but also the cell density due to increased communication. Experiments confirm this prediction, showing that cell density modulates the collective sensory response. We further implicate cell-cell communication by coculturing the fibroblasts with cancer cells, which we show act as "defects" in the communication network, thereby reducing the oscillation propensity. These results suggest that multicellular networks sit at a point in parameter space where cell-cell communication has a significant effect on the sensory response, allowing cells to simultaneously respond to a sensory input and the presence of neighbors.

A malignant cellular network in gliomas: potential clinical implications.

The recent discovery of distinct, ultra-long, and highly functional membrane protrusions in gliomas, particularly in astrocytomas, extends our understanding of how these tumors progress in the brain and how they resist therapies. In this article, we will focus on ideas on how to target these membrane protrusions, for which we have suggested the term "tumor microtubes" (TMs), and the malignant multicellular network they form. First, we discuss TM-specific features and their differential biological functions known so far. Second, the connection between 1p/19q codeletion and the inability to form functional TMs via certain neurodevelopmental pathways is presented; this could provide an explanation for the distinct clinical features of oligodendrogliomas. Third, the role of TMs for primary and potentially also adaptive resistance to cytotoxic therapies is highlighted. Fourth, avenues for therapeutic approaches to inhibit TM formation and/or function are discussed, with a focus on disruption (or exploitation) of network functionality. Finally, we propose ideas on how to use TMs as a biomarker in glioma patients. An increasing understanding of TMs in clinical and preclinical settings will show us whether they really are a long-sought-after Achilles' heel of treatment-resistant gliomas.

Linked in: immunologic membrane nanotube networks.

Membrane nanotubes, also termed tunneling nanotubes, are F-actin-based structures that can form direct cytoplasmic connections and support rapid communication between distant cells. These nanoscale conduits have been observed in diverse cell types, including immune, neuronal, stromal, cancer, and stem cells. Until recently, little was known about the mechanisms involved in membrane nanotube development in myeloid origin APCs or how membrane nanotube networks support their ability to bridge innate and adaptive immunity. New research has provided insight into the modes of induction and regulation of the immune process of "reticulation" or the development of multicellular membrane nanotube networks in dendritic cells. Preprogramming by acute type 1 inflammatory mediators at their immature stage licenses mature type 1-polarized dendritic cells to reticulate upon subsequent interaction with CD40 ligand-expressing CD4(+) Th cells. Dendritic cell reticulation can support direct antigen transfer for amplification of specific T cell responses and can be positively or negatively regulated by signals from distinct Th cell subsets. Membrane nanotubes not only enhance the ability of immature dendritic cells to sense pathogens and rapidly mobilize nearby antigen-presenting cells in the peripheral tissues but also likely support communication of pathogen-related information from mature migratory dendritic cells to resident dendritic cells in lymph nodes. Therefore, the reticulation process facilitates a coordinated multicellular response for the efficient initiation of cell-mediated adaptive immune responses. Herein, we discuss studies focused on the molecular mechanisms of membrane nanotube formation, structure, and function in the context of immunity and how pathogens, such as HIV-1, may use dendritic cell reticulation to circumvent host defenses.

Dynamic Force Patterns Promote Collective Cell Migration

Embryonic wound repair is driven by collective cell migration into the wounded region. Contraction of a supracellular cable formed by actin and the motor protein non-muscle myosin II coordinates the cell movements that drive wound closure. We showed that, in Drosophila embryos, the actomyosin cable displays a heterogeneous pattern, with regions of high and low actin density. Mutants in which the distribution of actin is uniform around the wound display significantly slower wound healing. However, the mechanisms by which a non-uniform distribution of actin favors rapid wound repair are unknown. We used quantitative microscopy to investigate how the distribution of cytoskeletal molecules affects wound healing. We found that actin and myosin displayed matching heterogeneous distributions at the wound margin. Using laser ablation, we demonstrated that tension along the cable was correlated with actomyosin levels, indicating that contraction of the cable is non-uniform. A force balance showed that closure forces resulting at the interface between regions of high and low actomyosin contractility are greater than in regions of uniform contractility, suggesting that a non-uniform distribution of tension at the wound margin favors rapid wound repair. We developed an in silico model of wound repair, and we found that healing was faster when the pattern of tension along the wound margin was heterogeneous. Our model predicted that, to maintain a heterogeneous distribution of tension around the wound over time, the actomyosin pattern must change as cell boundaries deform. Consistent with this, we found that in vivo, myosin accumulates in segments of the wound margin that are stretched as a consequence of the contraction of adjacent, myosin-rich segments. Our results suggest that a non-uniform distribution of contractile forces along multicellular actomyosin networks generates mechanical signals that facilitate rapid network remodeling, and efficient collective cell movements.

Hydroxyproline O-arabinosyltransferase mutants oppositely alter tip growth in Arabidopsis thaliana and Physcomitrella patens.

SummaryHydroxyproline O‐arabinosyltransferases (HPATs) are members of a small, deeply conserved family of plant‐specific glycosyltransferases that add arabinose sugars to diverse proteins including cell wall‐associated extensins and small signaling peptides. Recent genetic studies in flowering plants suggest that different HPAT homologs have been co‐opted to function in diverse species‐specific developmental contexts. However, nothing is known about the roles of HPATs in basal plants. We show that complete loss of HPAT function in Arabidopsis thaliana and the moss Physcomitrella patens results in a shared defect in gametophytic tip cell growth. Arabidopsis hpat1/2/3 triple knockout mutants suffer from a strong male sterility defect as a consequence of pollen tubes that fail to fully elongate following pollination. Knocking out the two HPAT genes of Physcomitrella results in larger multicellular filamentous networks due to increased elongation of protonemal tip cells. Physcomitrella hpat mutants lack cell‐wall associated hydroxyproline arabinosides and can be rescued with exogenous cellulose, while global expression profiling shows that cell wall‐associated genes are severely misexpressed, implicating a defect in cell wall formation during tip growth. Our findings point to a major role for HPATs in influencing cell elongation during tip growth in plants.

Glioma: Tumour cell teamwork.

A study in Nature reports that astrocytoma cells form a multicellular network interconnected by distinct tumour microtubes that drive invasion, mediate cell–cell communication, enable self-repair and confer radioresistance.